Two hundred million people worldwide are affected by thyroid proliferative diseases (TPD), which include goiter, cancer and adenoma. Women are three times more susceptible than men and overall the incidence of thyroid dysfunction occurring in one in eight women is a sizable health issue. The thyroid is a vascularized tissue and one of the cellular mediators of neo-vasculature are bone marrow derived endothelial progenitor cells (CD31+, CD34+, VCAM+). BM-EPCs normally reside in the marrow but migrate to tissues in response to inflammation, injury or cancer and estradiol (E2) enhances this migration. We observed that estradiol (E2) enhances peripheral circulation and migration of BM-EPCs to tumor tissues, induces neo-vasculature and up regulates cell survival pathways, Akt and ERK, in an E2 dependent manner. These EPCs that migrate to tissues under the influence of E2 to induce vasculogenesis are novel targets of anti-estrogen therapy in TPD. We propose to test the activity of the anti-estrogen DIM in animal and cell culture models and in human patients using E2 regulated vasculogenesis and cell survival pathways, Akt and ERK, as targets of DIM action. The aims are to: I. Examine estradiol induced neovasculature using a xenograft animal model with orthotopic implantation of N-Thy-ori3-1(differentiated), B-CPAP (undifferentiated), KAT50TS goiter cell lines in ovariectomized (OVX) Balb/c/nu/nu mice [unreadable] E2 supplementation [unreadable] DIM incorporated in the diet. II. Examine the regulation of the activation of Akt and ERK pathway in BM-EPC and TPD cells by E2-ER multiprotein complexes and the possible molecular intervention targets of DIM. III. Determine if oral administration of an absorption-enhanced formulation of DIM (Bioresponse DIM) achieves adequate thyroid tissue bioavailability and examine DIM levels in blood and urine of patients. IV. Examine the status of activated Akt/ERK [unreadable] DIM in thyroid tissue and define the profile of E2 responsive DIM mediated molecular changes in TPD by gene array analysis followed by validation at the expression level. This basic translational research is directed to reduce possible unnecessary surgery in TPD using bioactive food component, DIM, and determining the cellular and molecular basis of the gender bias of TPD. PUBLIC HEALTH RELEVANCE: This translational research with a novel basic component is directed to reduce possible unnecessary surgery in thyroid proliferative diseases using bioactive food component, Diindolylmethane, DIM. Surgical tissues obtained will be used to analyze estrogen mediated functions that can shed light on the observed 3:1 gender bias in the incidence of this disease in women.